RESUMO
A new compound library that contained 20 hinged benzimidazole-coumarin hybrids and their ß-d-ribofuranosides was established. The anti-hepatitis C virus (HCV) activity of all novel coumarin derivatives, which were obtained by use of organic synthetic methods, was tested. Two of these hybrids exhibited appealing EC50 values of as low as 3.0 and 5.5 µM. The best selectivity index was 14. The incorporation of a d-ribofuranose into the hinged hybrids provided the corresponding nucleosides with the ß configuration, one of which inhibited HCV replication with an EC50 value of 20 µM. Additionally, the structure-activity relationship is elucidated on the basis of the functional groups that were attached to the nuclei of benzimidazole, coumarin, and ribofuranose of the hybrids.
Assuntos
Antivirais/química , Benzimidazóis/química , Cumarínicos/química , Glicosídeos/química , Antivirais/síntese química , Antivirais/farmacologia , Linhagem Celular Tumoral , Cumarínicos/síntese química , Cumarínicos/farmacologia , Relação Dose-Resposta a Droga , Furanos/química , Glicosídeos/síntese química , Glicosídeos/farmacologia , Hepacivirus/efeitos dos fármacos , Humanos , Espectrometria de Massas , Modelos Químicos , Estrutura Molecular , Pentoses/química , Espectroscopia de Infravermelho com Transformada de Fourier , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacosRESUMO
For establishment of the structure-activity relationship, 19 heterobicycle-coumarin conjugated compounds with the -SCH(2)- linker were synthesized and found to possess significant antiviral activities. Prominent examples included imidazopyridine-coumarin 12c, purine-coumarin 12d, and benzoxazole-coumarin 14c, which inhibited HCV replication at an EC(50) of 6.8, 2.0, and 12 microM, respectively. The heteroatoms in bicycles and the substituent effect on coumarin played essential roles.
Assuntos
Antivirais/síntese química , Cumarínicos/síntese química , Hepacivirus/efeitos dos fármacos , Compostos Heterocíclicos com 2 Anéis/síntese química , Antivirais/química , Antivirais/farmacologia , Benzoxazóis/síntese química , Benzoxazóis/química , Benzoxazóis/farmacologia , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Cumarínicos/química , Cumarínicos/farmacologia , Hepacivirus/genética , Compostos Heterocíclicos com 2 Anéis/química , Compostos Heterocíclicos com 2 Anéis/farmacologia , Humanos , Imidazóis/síntese química , Imidazóis/química , Imidazóis/farmacologia , Modelos Moleculares , Purinas/síntese química , Purinas/química , Purinas/farmacologia , Piridinas/síntese química , Piridinas/química , Piridinas/farmacologia , RNA Viral/efeitos dos fármacos , Relação Estrutura-Atividade , Replicação Viral/efeitos dos fármacosRESUMO
Nineteen new conjugated compounds were successfully synthesized by a one-flask method from benzimidazole and coumarin derivatives. A methylenethio linker was used to connect these two kinds of derivatives. In addition, substituted benzimidazol-2-thiones were also coupled with beta-D-glucose peracetate; the resultant glucosides were further converted to the corresponding 2-(methylthio)coumarin derivatives. Their activity against the hepatitis C virus was tested; two of the most potent compounds 2-[(6'-bromocoumarin-3'-yl)methylenethio]-5-fluorobenzimidazole (4i) and its derivative 1-[(2'',3'',4'',6''-tetra-O-acetyl)glucopyranos-1''-yl]-2-[(6'-bromocoumarin-3'-yl)methylenethio]benzimidazole (7c) showed EC(50) values of 3.4 microM and 4.1 microM, respectively. At a concentration of 5.0 microM, compound 7c inhibited HCV RNA replication by 90% and had no effect on cell proliferation. Given these data, a structure-activity relationship was established.